SFTSV induces liver ferroptosis through m6A-related ferritinophagy

作者：Bingxin Liu, Xiaoyan Tian, Linrun Li, Na Jiang, Min Cheng, Jin Zhu, Zhiwei Wu · 发表于：Autophagy · 年份：2025 · DOI：10.1080/15548627.2025.2503564 · 被引用次数：15 · 研究领域：RNA modifications and cancer、HVDC Systems and Fault Protection、Viral-associated cancers and disorders

Severe fever with thrombocytopenia syndrome (SFTS) is a widely prevalent infectious disease caused by severe fever with thrombocytopenia syndrome virus (SFTSV). SFTSV infection carries a high mortality rate and has emerged to be a public health concern. SFTSV infection could induce many classical cell death pathways. Ferroptosis, a novel iron-dependent form of regulated cell death, is shown to participate in various biological processes and is considered as a new therapeutic target. In the current study, we reported that SFTSV infection perturbed the classical redox cycle by downregulating the expression of GPX4, SLC7A11 and GSH, and increasing the level of reactive oxygen species (ROS) and malondialdehyde (MDA). Interestingly, we observed that the elevation of ATG5 mRNA m6A modification after SFTSV infection and mutation of the m6A-sites significantly rescued SFTSV infection-induced ferritinophagy. We further found that the NSs protein of SFTSV played a major role in driving the ferritinophagy. Finally, we found that ferroptosis inhibitor ferrostatin-1 prevented ferroptosis and suppressed SFTSV infection both in vitro and in vivo models. In summary, our study demonstrated that SFTSV infection could induce ferroptosis in liver, and m6A modified ATG5 mediated ferritinophagy to facilitate this process. Targeting ferroptosis may serve as a potential therapy for the treatment of SFTS.Abbreviations: ATG5: autophagy related 5; Baf-A1: bafilomycin A1; Fer-1: ferrostatin-1; Fe2+: fer...